Use of n-acetyl-d-glucosamine in the manufacture of pharmaceutical useful for suppressing side-effect of radiotherapy and chemotherapy

ABSTRACT

The present invention has disclosed a use of N-acetyl-D-glucosamine in the manufacture of a medicament for inhibiting the side effect of radio-chemical therapy, the medicament with N-acetyl-D-glucosamine as main active component can be used to inhibit the side effect of radio-chemical therapy of cancer patients, with an effective rate up to 85%.

TECHNICAL FIELD

[0001] The present invention relates to the use ofN-acetyl-D-glucosamine and pharmaceutical acceptable salts thereof inthe manufacture of a medicament for inhibiting the side effect ofradio-chemical therapy.

BACKGROUND ART

[0002] After accepting radio-chemical treatment, patients with neoplasmoften have marrow inhibition, hemogram variation, anemia, leucocytereduction, protein synthesis inhibition and other reflections indysfunction of metabolism, and they will be quickly accompanied withsystematical side effects of radio-chemical therapy: nausea, vomiting,lack energy, appetite decreasing, loss of the hair and so on, theseverer may have acute exhaustion or respiratory distress; as leucocytesdecreasing may lead to immune dysfunction, systematical infection islikely to happen; furthermore, with the disturbance of the production ofimmune cells, most of the patients with neoplasm are finally dead fromthe whole body exhaustion, cachexia, infection and so on, these arealmost resulted from the side effect of radio-chemical therapy.Therefore the control of side effect of radio-chemical therapy iscontributed to the long period therapy of neoplasm and to strengthen thesupport ability of neoplasm patient to the therapy; at the same time,lighten the patient's pain in the course of treatment, and avoid aserious of complication caused by neoplasm. At present, supportingtherapies commonly used clinically are mainly symptomatic treatments:for instance, when the patient lacks energy□ administration of energymixture is adopted; when water electrolyte is disordered, supplyingwater electrolyte is adopted; when vomiting is serious, anti-vomitingmedicine is administrated; when the patient is infected,anti-inflammation therapy is used, and so on. The effects of thesesymptomatic treatments do not have good effect. The side effect afterradio-chemical therapy almost happens to the each patient with neoplasmwho has been treated, making them suffered from pain, and this is a bigproblem in the neoplasm treatment. Therefore, a medicament capable ofinhibiting the side effect caused by radio-chemical therapy is quiteneeded in the field of neoplasm treatment.

[0003] In the research of “bio-waves” theory, the present inventor hasset up a bacterial wave growth model. Through researching, it is knownthat this wave is of its intrinsic regulation mechanism: some chemicalsubstances are able to participate the regulation in the bio-waveprocess, so as to transform an abnormal periodic slow wave into a normalphysiological chaotic quick wave, and this kind of substances are knownas promoting wave factors. Through separating, purifying andidentifying, it is determined that one of the factors isN-acetyl-D-glucosamine, the promoting wave function of which is shown inlubricating and protecting the cell. Many biochemical and physiologicalprocess of human body need the participation of the promoting wavefactors, and it would lead to an abnormal state, if this kind ofpromoting wave factors is lacked in the living body.

[0004] N-acetyl-D-glucosamine is a chemical reagent. From the 1990's, itis continually used to treat pericementitis (WO9102530A1),microbiological infection (WO9718790A3), intestinal inflammation(WO9953929A1), cornea disease (JP10287570A2), hypertrophy of theprostate (U.S. Pat. No. 05,116,615) and so on. It is also applied incosmetology (JP59013708A2), shampoo preparation (JP2011505A2), tissuegrowth regulation agent (WO/A 8 702244), and etc., but it has not beenused in the manufacture of a medicament for inhibiting the side effectof radio-chemical therapy.

[0005] Contents of the Invention

[0006] The applicant of the present invention finds thatN-acetyl-D-glucosamine and pharmaceutical acceptable salt thereof areable to effectively inhibit the occurrence and serious degree of theside effect of radio-chemical therapy.

[0007] Therefore, the present invention is related to the use ofN-acetyl-D-glucosamine and pharmaceutical acceptable salt thereof in themanufacture of a medicament for inhibiting the side effect ofradio-chemical therapy.

[0008] On the other hand, the present invention is related to a methodfor inhibiting the side effect of radio-chemical therapy, includingadministrating to a patient who is in need thereof an effective amountof N-acetyl-D-glucosamine or pharmaceutical acceptable salts thereof.

[0009] The structure of N-acetyl-D-glucosamine is as follows:

[0010] N-acetyl-D-glucosamine can be purchased in the market or preparedaccording to known methods. For instance, patent application WO97/31121has disclosed a method for preparing N-acetyl-D-glucosamine from chitinby enzyme method, Japanese patent application JP63273493 has disclosed amethod in which chitin is partiallyhydrolyzed into N-acetyl-chitose, andthen it is treated with enzyme to obtain N-acetyl-D-glucosamine.

[0011] The pharmaceutical acceptable salts of N-acetyl-D-glucosaminethat can be mentioned are the salts formed with pharmaceuticalacceptable acids, for instance, the salts formed with inorganic acids,such as hydrochloride, hydrobromide, borate, phosphate, sulfate sulfiteand hydrophosphate, and the salts formed with organic acids, such ascitrate, benzoate, ascorbate, methyl sulfate, naphthalene-2-sulfonate,picrate, fumarate, maleate, malonate, oxalate, succinate, acetate,tartrate, mesylate, tosylate, isethionate, α-ketoglutarate, α-glycerylphosphate and glucose-1-phosphate.

[0012] The compound of formula (I) or pharmaceutical acceptable saltsthereof can be used as active agent to be combined with many kinds ofpharmaceutical acceptable excipients or/and carriers, by the way ofmixing, granulation, tableting, sugar coating or film coating and so on,it can be formulated into liquid or solid preparations, so as to be usedto inhibit the side effect of radio-chemical therapy

[0013] The compound of formula (I) or pharmaceutical acceptable saltsthereof can be administrated parenterally, for instance, by intraveininjection, intramuscle injection, or orally. The dosage dependents onthe age, body weight, disease condition of the patient, theadministration manner and the specific method of radio-chemical to treatthe neoplasm. The compound of formula (I) or pharmaceutical acceptablesalts thereof can be administrated several days (for instance 3˜10 days)before performing the radio-chemical therapy for anti-neoplasm, thenadministrate the medicament in combination with radio-chemical therapyfor anti-neoplasm; or directly administrate the medicament with thecombination of radio-chemical therapy for anti-neoplasm; it is alsoeffective to administrate the said medicament after the radio-chemicaltherapy for anti-neoplasm is started and the side effect has beenemerged. A suitable dosage for the adult to be administrated is about200˜10000 mg/day, intravein injection preferably is once daily, oral orintramuscle injection preferably is three times daily. It is suggestedthat seven days is a course of treatment, and continue theadministration for 2˜3 courses of treatment.

[0014] Conventional methods can be used to formulate the phmarceuticalcompositions in the form of suitable pharmaceutical preparations, forinstance, the preparations in the form of liquid for intravein injectionor oral administration may use aseptic water or aseptic saline solutionas carriers. The suspensions or solutions for intramuscle injection mayuse aseptic water, olive oil, ethyl oleate, diols and other medicallyacceptable carriers. In the form of solid formulation for oraladministration, such as tablet or capsule, beside of the compound offormula (I), it may also include diluent, such as lactose, glucose,cellulose, starch, lubricant such as silica, talc, magnesium stearate orcalcium stearate, and /or polyglycol; binder such as starch, Arabic gum,methyl cellulose, carboxymethyl cellulose, polyvinylpyrrolidone;depolymerizing agent such as starch, alginic acid, aliginate, starchsodium glycolate; foaming mixture; colorant; sweetener; lubricant suchas lecithin, polyethenoxy ether and so on. Said preparations can beprepared by the known processes, such as mixing, granulation, tableting,sugar coating or film coating and so on.

[0015] Though having no intention to be limited by any theories, thepresent inventor thinks that, the continuous wave of normal organismexecutes the physiological function by the way of rhythmical lifeactivity of tissue cell. This wave process is a chaos process, by whichthe adaptation to the outside world can be maintained. Chaos waveprocess of the organism dependents upon the systematical synergism andunification of various tissues. In the process of treating neoplasm byradio-chemical therapy, not only the enzyme is subjected to influencesynthetically, but the function of existing enzyme protein also haveobstacles, furthermore, the metabolic activity is affected, to make thesystematical coupling oscillation dispersed, incapable of emerging greatfunction activity, and showing a non-rhythmical process of lifeactivity, that is, a successive reaction, leading to various sideeffects. Thus, the control of radio-chemical therapeutic side effectwould be focused on protecting the function of existing protein.N-acetyl-D-glucosamine possesses a characteristic of promotingbio-waves, and it is believed that, through regulating the oscillationof enzyme protein, the systematical function of the organism and theprocess of recovering rhythm of organism can be regulated. On one hand,it exerts the systematical effect to organism for resisting thestimulation of unfavorable factors, adapts to the outside world; on theother hand, it regulates the oscillation of enzyme protein, removeunfavorable influence of the environment, moreover, relieve or controlthe side effect of radio-chemical therapies.

OPTIMAL MODE FOR CARRYING OUT THE INVENTION

[0016] The following experimental examples are used to illustrate thepromoting wave function, low toxicity, and the effect for inhibiting theside effect of radio-chemical therapy, of the compound of the presentinvention (the compound of formula (I)).

[0017] I. Promoting wave test of the compound of formula (I)

[0018] 1. Experimental materials and method:

[0019] 1.1 Samples: pure compound of formula (I)

[0020] 1.2 Experimental materials:

[0021] Strain: Proteus Mirabilis (which should comply with the followingbiological reaction characteristics: dynamics (+), urease (+), lactose(−), glucose (+), H₂S (−), phenylalanine deaminase (+).

[0022] Culture medium: modified LB culture medium (the components of thecomposition are: trytones of 1%, yeast extract of 0.5%, sodium chloride1%, glucose of 0.1%, TTC of 0.002% and pH=7.2˜7.4).

[0023] 1.3 Experimental method:

[0024] The Proteus Mirabilis were inoculated at the center of LB plate,incubating at 37° C. for 9 hours, then there were concentric ringsemerged, which were extended outward continually with an interval of 3hours, and this was taken as a control; adding the compound of formula(I) with final concentration of 0.5% onto the LB plate, The ProteusMirabilis were innoculated by the same method, cultured at 37° C., andthe result showed that not only the concentric rings formed with aninterval of 3 hours were emerged, comparing with the control, it can beseen that there were also many fine waves on each ring emerged.

[0025] 2. Experimental results and evaluation:

[0026] The experiment adopts a bio-wave model which is used to researchthe promoting wave function of the compound of formula (I). It can beseen from the result that the compound of formula (I) was not only ableto cause bacterial cell to reveal a normal bio-wave characteristic, butalso cause the wave reveal finer wave mode, and these indicated that thecompound of formula (I) have promoting function to bio-waves, and thepromoting wave function is able to participate the reparation andre-distribution function of the cells of skin.

[0027] II. Toxicological Test of the Compound of Formula (I), Including:

[0028] 1. acute toxicity test: including tests of administratingmedicine by oral, Intravenous injection and maximum limit amount foradministration;

[0029] 2. Ames test;

[0030] 3. micronucleus test of bone marrow cell of mouse;

[0031] 4. abnormal sexual test for the sperm of mouse;

[0032] 5. abnormal aberrance test for the chromosin of mouse's testis;

[0033] 6. chronic lethal test;

[0034] 7. subchronic toxicity (feed for 90 days) test;

[0035] 8. traditional aberrance-inducing test;

[0036] The results from these tests show that in the acute toxicity testof the compound of formula (I), the dosage more than 2 g/kg is taken,which is 300 times than the injection dosage for human being, but theacute toxicosis reaction had not appeared yet; in the long-periodtoxicity test, the maximum dosage has reached up to 1 g/kg, and afterthe treatment and observation for four weeks, there is no toxicosisreaction yet; and in the reproduction test, the mouse was fed withroutine dosages from 7 mg/kg for 3 generations, it has been proved thatthe compound of formula (I) has no influence on the pregnancy, birth,nurse and the growth of baby mice, so it is proved that the compound offormula (I) is a substance without toxicity.

[0037] III. Observation of Curative Efficiency.

[0038] It is known from observation of the clinic trial that thebio-wave capsule (containing 600 mg of N-acetyl-D-glucosamine in eachgranule) of the present application has an excellent effect to controlthe side effect in the process of radio-chemical therapy for treatingthe patient suffered from the leukaemia, Hodgkin's disease and theneoplasm of liver, stomach and so on, with a total effective rate of85%, a part of typical cases are as follows:

[0039] 1. Mr. Zhang, male, suffered from leukaemia, after radio-chemicaltreatment, appeared uncomfortable phenomenons of weak, lacking energyall over the body, appetite decreasing, often vomiting and so on, so thecondition of his body was very worse. A week after administrating thebio-wave capsule of the invention, his can eat as the normal, meanwhilethe dreaminess, palpitation and other bad sleeping situations wererelieved. After that, continuously administrate the medicine, his lackof energy was recovered while and the number of catching cold wasremarkably decreased.

[0040] 2. Ms. Chen, come from Nanchong, Sichuan province, female,suffered from stomach cancer, after radio-chemical treatment, her bodybecome thin, the immunity condition was reduced, companied with appetitediminishing and bad emotion. Administrating the bio-wave capsule of theinvention 3 times a day, 1˜2 capsules each time, after a week, herfeeling gradually became better, and some bad symptoms was improvedwithout any side effect, continuously administrate the medicine.

1. A use of N-acetyl-D-glucosamine in the manufacture of a medicamentfor inhibiting the side effect of radio-chemical therapy to the cancerpatients.
 2. The use according to claim 1, wherein said medicament issuitable for administration by oral, intravein and intramuscle.
 3. Theuse according to claim 1 or 2, wherein said medicament is administratedto the adult patients with a dosage of 200˜10000 mg ofN-acetyl-D-glucosamin daily.